Delivery of pharmaceuticals to target organs in a human organism is one of the basic problems in medicine, pharmaceutics and biotechnology, i.e. in the areas related to treatment of various diseases.
Furthermore, it is often important and even necessary in diagnostics and treatment of diseases to carry out controlled release of one or several compounds into an organism of a patient, in particular, organism of a mammal, for a long period.
However, traditional methods of administration of pharmaceuticals, such as oral intake or direct injection of a pharmaceutical, do not provide long time controlled release of the drug. Instead of providing a controlled concentration of a pharmaceutical during a long period of time, these methods of administration result in the instant release of a drug into an organism and subsequent relatively fast decrease of the concentration in blood. However, in many cases, instant release of a pharmaceutical with subsequent decrease of its level in blood is often not a preferred way of administration. The effectiveness of treatment can be much higher, when the concentration of a pharmaceutical in blood is maintained at a predetermined fixed level during a long period of time or when a pharmaceutical is released at a predetermined moment. Furthermore, instant administration of a pharmaceutical into an organism may cause the increase of its concentration, which exceeds the abilities of active sites to digest it, and may exceed capacity of the metabolic and excretory mechanism of a living organism. If the level of pharmaceutical remains increased, it may affect tissues or organs.
On the contrary, continuous controlled release of a pharmaceutical for a long period of time has essential clinical advantages. For example, when treatment with a pharmaceutical should proceed for a long period of time, administration of a pharmaceutical by intake or direct injection is connected with inconveniences of necessity of recurrent administration. Moreover, when treatment requires recurrent pharmaceutical administration, there is a possibility that a patient forgets or purposely does not take a pharmaceutical. If an opportunity of continuous administration of a pharmaceutical will be provided, so its controlled release during a long period of time will be carried out, necessity of recurrent administration will be eliminated.
Traditional methods of administration of medical materials deeply in biotissues are syringe or needleless injectors, which represent containers with pharmaceutical fluid, wherefrom medical fluid through a syringe needle (or through a throttle hole of injector) under high pressure flows deep in biotissues through broken skin.
However, this classical method of administration of pharmaceuticals does not provide its purposeful delivery to target organs, and neither its controlled release into an organism.
A method of administration (delivery) of a pharmaceutical by applying a medicated pad on a nidus with simultaneous stem of blood flow in the nidus area, and ultrasonic sound exposure for 30 minutes, with a periodic loosing of a tourniquet was disclosed in SU 556805, May 5, 1977.
From SU 882528, Jan. 4, 1979, other method of administration of pharmaceuticals in an organism by a device containing carrying case, container with a medical fluid and an ultrasonic converter, is known. The delivery of pharmaceutical is performed by contact action of high frequency ultrasound on a biotissue in area of pathological nidus through a wad with a pharmaceutical.
Disadvantages of the mentioned methods are that the high-frequency ultrasound, having small amplitudes of radiator head, performs only micromassage of biotissue surface, which does not provide sufficient infiltration of a medical material through an integument, and depth of penetration does not exceed the thickness of skin epidermis.
The method of delivery (administration) of pharmaceuticals to a wounded surface, which comprises spraying of a medical solution in the form of a medical aerosol torch, treated with ultrasound (SU 1106485, Oct. 22, 1982), is known. This method provides penetration of pharmaceuticals only in biotissue areas with a broken horny layer of skin epidermis. Delivery of pharmaceuticals deep into biotissues through intact integument is inconvenient since the horny layer of epidermis serves as a protective barrier, virtually non-permeable for liquids coming from external media.
From RU 2076746, Apr. 10, 1997 the method of administration of pharmaceuticals is known, which comprises spraying of a biotissue with a medical solution in the form of a medical aerosol torch, treated with ultrasound vibration frequency of 44-66 kHz and radiator head vibration amplitude of 25-35 microns and treatment of a biotissue by low-frequency ultrasound with frequency of 26.5 kHz and vibration amplitude of 40-50 microns at exposure 5-10 s sm−2. According to the method, a local heating zone is made preliminary above the biotissue surface with temperature 40-50° C., which induces diaphoresis from it. Then the biotissue is promptly cooled with a torch of an aerosol of medical material down to 20-25° C., and treatment with low-frequency ultrasound is performed after spraying a pharmaceutical, and simultaneously with ultrasonic an alternating magnetic field is applied with magnetic induction amplitude of 30-40 mT.
The said methods are designed only for delivery of a medical (therapeutic) agent to external, generally wounded surface of a biotissue, i.e. have limited applications.
From RU 2250102 C2, Apr. 20, 2005 the method of drug administration is known, with directed transfer and subsequent release of a bioactive compound into organism of animals after contact to mucous membranes, especially as method of oral and intrapulmonary administrations. Bioactive compound is encapsulated into a microcapsule made of biocompatible polymer or a copolymer which can pass through a gastrointestinal tract and be conserved on a mucosal surface without destruction, or being exposed to it insignificantly. This provides intake of a bioactive compound into Peyer's patches or others lymphatic tissues associated with mucous membrane and penetration into them in initial effective quantities. The term “biocompatible polymeric material” is designated for a polymer which is not possessing toxicity, carcinogenic or inflammatory action in an organism. It is desirable, that an indifferent polymeric material of microcapsules was exposed to biodegradation, i.e. was decomposed during physiological processes to products which are not accumulated in tissues and excreted from an organism. Microcapsules should have such dimensions and physical and chemical properties, which would provide their effective selective intake into Peyer's patches. In the invention the problems of the directed transfer of bioactive compounds to Peyer's patches and other tissues, associated with mucous membranes and inclusions, are solved.
However, the known method concerns only the method of oral administration of an antigen to animals at which it reaches Peyer's patches and is intaken into them, stimulating, thus, immune system of mucous membrane, without loss of immunifacient activity during transport along a gastrointestinal tract.
The known method of oral administration of a bioactive compound to animals provides its transport and intake into Peyer's patches, for establishment of local or systemic concentration of a drug, but concerns the delivery of a certain pharmacological form of a therapeutic agent, containing a bioactive ingredient and polymeric or copolymeric inert material, preferably exposed to biodegradation, which is applicable for transport to mucous membranes by means of this method.
Various implants have been developed for achievement of a required level of a pharmaceutical in blood during a long period of time, which provide continuous controlled release when administered to a patient.
Implants contain active material or a pharmaceutical in combination with a polymeric system of delivery, which controls release of the pharmaceutical. The pharmaceutical is physically encapsulated in a polymeric matrix and released from a matrix by diffusion through polymer or at break of a polymeric matrix. Generally, polymeric system of delivery is a biocompatible resolving polymeric matrix. The polymeric matrix, however, is not always resolving. When not resolving implants are used, surgical removal of the implant is required after release of a pharmaceutical.
A variety of matrices have been developed for controlled release of a pharmaceutical, including polymeric matrices made of hydrogels, gelatin, cellulose, organopolysiloxane rubbers, polyurethanes, wax, poly(vinyl alcohol), polyglycolic acid and lactic acid polymer. Often polymeric matrix represents a copolymer of lactic acid and a glycolic acid (“PLGA”, polymer of lactic glycolic acid). Pharmaceutical is released from the PLGA matrix at matrix hydrolytic cleavage. When polymeric matrix decomposes, the pharmaceutical is released into adjacent fluids of an organism.
Rate of release of a pharmaceutical depends on the set of variables, including, for example, choice of polymeric matrix, concentration of pharmaceutical in the matrix, size and form of an implant, method of implant manufacturing, surface area of implant and pore size.
From RU 2272617, Mar. 27, 2006 the method of controlled release of a pharmaceutical into an organism of a patient is known, comprising administration of a pharmaceutical implant, which includes microparticles of one or several pharmaceuticals dispersed in a resolving polymer, which microparticles are sufficiently interrelated with each other to support the preset implant form without complete sintering of polymer, and in which implant breaks up to separate microparticles at certain time after administration. Such implant is administered intramuscularly or subcutaneously.
Nowadays various physical methods of medical treatment are widely spread in medicine, for example, the methods of magnetotherapy, which are based on action of electromagnetic field and use of various magnetic materials.
For example, from U.S. Pat. No. 5,236,410, 1993 a method of tumors treatment is known, based on the use of magnetic particles together with a therapeutic agent and influence of electromagnetic field. The method comprises selective catheterization of hepatic artery or renal artery at kidney tumor. The dispersion of barium hexaferrite or strontium in oil solution of Dioxadet is injected through a catheter to a tumor area by an external magnetic field under control of a roentgenoscopy. At large tumor sizes an arterial blood stream afterwards is reduced with a metal spiral. In 1-3 days the tumor is attacked with a microwave electromagnetic field or ultrasound for achievement of temperature in the tumor 43-43.50° C. and the treatment continues during 5-45 minutes at this temperature. Puncture biopsy of the tumor is performed in 6-7 and in 15-20 days and, again, in 3-6 months, in presence of viable tumor cells the hyperthermia is repeated.
Such method due to simultaneous impact on tumor cells of a chemical drug and hyperthermia restricts a possibility of release of tumor cells and cellular debris in general blood stream, thus, reducing probability of metastases and intoxication of an organism. Radio-opacity of embolisate allows to control the tumor state and, if necessary, to carry out repeated courses of hyperthermia.
Accordingly, and also in view of other not less important factors, magnetoactive compounds including pharmaceuticals have wide applications.
Delivery of pharmaceuticals to target organs in a human organism is one of the fundamental problems of, for example, chemotherapy. One of the approaches to this problem, as follows from the aforesaid, is the use magnetosensitive carriers for pharmaceuticals, which administrated into blood vessels, transported by blood flow and are localized in a preset place by means of magnetic field. Magnetosensitive and biocompatible nanospheres are known, designed for injection into vessels and localization in a certain place, which consist of a carbohydrate crystalline matrix and magnetic particles (application WO 83/01738, 1983). Carbohydrate crystalline matrix is starch, glycogen, dextran or their derivatives. The known carrier possesses insufficient hydrolytic and enzymatic stability.
Magnetic composite microspheres are also known, based on a net organosilicon polymer, which consist of a core representing magnetizable material with sizes less than 300×10−4 micron, evenly distributed in a net of polysilsesquioxane, containing more than 2 vinyl groups in a molecule and probably ionogenic and/or non-vinyl active group and a surface layer, representing net silicon organic polymer—application EPO 0435785, 1991. However the polymeric matrix of the known carrier possesses insufficient biocompatibility.
Other method of intravenous administration of biologically destructed magnetosensitive carrier, containing magnetic particles, covered with a polymeric matrix (U.S. Pat. No. 4,247,406, 1981) is known. The carrier contains Fe3O4 as magnetic particles and albumin as a polymeric covering, with mass ratio 5-350 of Fe3O4 to 100 of albumin. The carrier provides rather fast release of a medical or biologically active material in an aqueous medium or blood, and if the microspheres are not attacked with proteolytic enzyme, the carrier conserves the integrity and activity for up to 48 hours.
The method has the disadvantage, as the used carrier has insufficient hydrolytic and enzymatic stability, and magnetizability.
The use of controlled methods of delivery of medical (therapeutic) agents by means of, for example, magnetic carriers is of high significance, as it allows delivery of a pharmaceutical to target organ under applied external magnetic field. The use of magnetic pharmaceuticals, generally, reduces toxicity of medical material, and also provides longer duration of action which allows to reduce doses of medical material. Furthermore, the present work has the theoretical importance, specifically it allows to propose, what pharmaceuticals (their structural analogues) may be used for administration of magnetoactive compounds.
Methods of administration of magnetoactive pharmaceuticals are known, based on encapsulation of an active material and magnetic component into a binding shell (Giano Guan, Lin Shi yin, Zhang Xizeng, Zhongguo uaxue zazhi, Chin Pharm. G.-1996.-31, V 1.-p. 27-29; T. M. Shvets, N. F. Kushchevskaja, E. V. Klochko, Vrach. Delo (ikap. CπpaBa), 1997. p. 37-78) and on sorption of pharmaceuticals on a surface of magnetic carrier particle (RU 2030618 and RU 2068703), and on administration of a magnetic component and formation on its surface of a polymeric covering into which a medical material is administered (RU 2065302; Formulation and characterization of magnetic poly(glutaraldehyde) nanoparticles as carriers for poly(1-lysinemethotrexate)/Hung C. T., Mcleod A. D., Gupta P. K.//Drug Dev. And Ind. Pharm.-1994.-16, 3. p. 509-521.; N. L. Lukjanchikova, L. I. Autenshljus, N. A. Brusentsov, Bull. Sib. Branch of AMS USSR, 1989.-1. p. 17-21). Highly effective pharmaceuticals are known, obtained by pelletizing of mixture of magnetic materials, antitumor pharmaceuticals (Fluorouracil, Bleomycin, Chromomycin) and adhesive water-soluble polymers (hydroxypropyl cellulose etc.) (Application 2-9813 Japan), and also drugs containing magnetic materials, along with their uses (Ito Ritsuko, Matida Isikharu, Yaminami Takanari.-6339599//J. of Chem. Abstr. 19. ChemistryVINITI-1991-60.-p. 76).
The method of delivery, for example, of Adriablastin with a magnetic carrier (RU 2018312, Aug. 30, 1994) is known. Technology is implemented by placing of Adriablastin on a ferromagnetic in aqueous solution with the use of freshly prepared magnetite or powder of reduced iron, as a ferromagnetic, which is preliminarily activated with 0.05 N solution of inorganic acid. Magnetite and aqueous solution of a therapeutic agent are prepared separately, and then deposition of the pharmaceutical on ferromagnetic powder is performed. This step is carried out as follows: a certain volume of aqueous suspension of synthetic magnetite or activated powder of iron, containing 1 g of dry ferromagnetic, is placed into reactor vessel supplied with a stirrer. Aqueous solution of Adriablastin with concentration 1−5×10−4 M is added to the reaction mixture and stirred at 20° C. for 0.5-4 minutes. The resulted product separated from excess of aqueous medium by decantation.
Other method of delivery of pharmaceuticals with the use of magnetosensitive carrier is known. Magnetosensitive carrier consists of microcapsules prepared from high molecular weight organic compounds with magnetosensitive particles incorporated in them. A pharmaceutical is placed on the carrier and is used for treatment of tumor diseases with utilization of directed transport of an agent to a nidus by means of external source of magnetic field (K. Widder et al., J. of Pharm. Sci., 1976, v. 68, N 1, pp. 79-89).
However, the known magnetocontrolled microcapsules have not found any real life application in oncologic practice for some reasons:                administration of magnetocontrolled microcapsules is associated with serious technological problems;        the problem of standardization of the microcapsules, obtained by the known method, has not been solved;        the problem of industrial manufacturing of microcapsules has not been solved.        
Moreover, the method of administration of the known microcapsules assumes the use of aggressive media and/or high temperatures, which are incompatible with many pharmaceuticals. The essential component of the known microcapsules, high molecular weight organic compounds, represents a risk of development of allergic responses, population susceptibility to which increases during last years.
From RU 2143266, Dec. 27, 1999 the method of delivery (and treatments) of a pharmaceutical to a human organism is known with the use of magnetocontrolled carrier, comprising injection through a catheter connected to vessels, feeding a tumor tissue, pharmaceuticals, sorbed on ferrocarbon particles; localization of an agent in a nidus by means of a magnet placement on body surface projected on the tumor. The use of the magnet provides a gradient of magnetic density not less than 3 T m−1; and suspension of an antitumor agent administered with rate not higher than 1-2 ml min−1 is used as a local chemotherapeutic and/or radiation antitumor agent. Localization of an agent in metastases takes place due to natural tropism of ferrocarbon particles to places of localization of tumor conglomerates, and after its magnetic localization in an area of tumor growth it is gradually biotransformed and the resulted complex compounds stimulate hemopoiesis and atrepsy.
However, the present method in a greater degree concerns delivery of a pharmaceutical at treatment of tumor diseases.
The method of delivery of pharmaceuticals controlled by magnetic field is known, in which stainless steel SUS 316L, covered with hydrogel of magnetic gelatin is used (Li-Ying Huang et al, Abstract PSTu-L-494 of ICM 2006, Kyoto, Japan, Aug. 20-25, 2006). Gelatin is intensively used in systems of delivery of pharmaceuticals due to its good swelling capacity and biocompatibility. Pore size of hydrogel may be controlled through a change of polymer composition, linkage conditions and concentration of magnetic precursor. Model pharmaceutical was introduced into gel film after application of magnetic field. Rate of release of the pharmaceutical noticeably decreased in comparison with the case of absence of the field. Apparently, it may be associated with denser configuration of hydrogel caused by aggregation of magnetic nanoparticles and decrease of gel pore size. The gel exhibited rather low cytotoxicity for L 929 cell line, which indicates its good biocompatibility. The used method shows good possibilities for biomedical devices as cardiovascular stent with delivery of pharmaceuticals, and also for tissue engineering.
Good example of application of heat-sensitive polymers for delivery of cells is the use of copolymer of N-iso-propyl acrylamide and acrylic acid for delivery of chondrocytes at maintenance of cartilage (J. Biomed. Mater. Res. A, 69, 2, 367-372, Au, etc). In such system temperature may change under applied magnetic field.
It is known, that heat-sensitive ferrofluids (type F 127), consisting, for example, from magnetic nanoparticles, covered with a shell from Pluronic F 127, may be used for desorption of pharmaceuticals controlled by a magnetic field (Ting-Yu Liu, et al, Abstract We A1-C2-3, ICM 2006, Aug. 20-25, 2006, Kyoto, Japan). It has been noted, that such F 127 ferrofluid forms gels at temperature above 23.8° C., which is noticeably below the one for pure Pluronic F 127 (40.5° C.). A pharmaceutical may be homogeneously distributed in F 127 ferrofluid below lower critical solution temperature and then at temperature above critical be encapsulated in the ferrogel. Heating of magnetic particles with alternating magnetic field may be used for formation of such gels (J. H. Park et al, J. Magn. Magn. Mater, 2005, v 293, p 328; D. H. Kim et al, J. Magn. Magn. Mater, 2005, v 293 p 320). Experiments have also shown that desorption of pharmaceuticals in similar gels may be also controlled by constant magnetic field. Release of vitamin B12 was increased by 20% after application of magnetic field to the gel
However, physical and chemical mechanisms leading to increase of desorption under applied constant magnetic field are unknown and, hence, cannot be controlled.
The method of utilization of alternating magnetic field, causing remagnetization of magnetic moments of particles and their subsequent heating is known and is used in hyperthermia.
Thus, there is a continuing necessity in providing novel compositions for controlled release rate drug delivery, for providing improved methods of delivery thereof to a human organism, and improved methods of manufacturing of drugs not only providing delivery of the active substance in a controlled way, but also the controlled release of the drug at a predetermined time and location in a patient's body.